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Telomere shortening, TP53 mutations and deletions in chronic lymphocytic leukemia result in increased chromosomal instability and breakpoint clustering in heterochromatic regions

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Abstract

Complex karyotypes are associated with a poor prognosis in chronic lymphocytic leukemia (CLL). Using mFISH, iFISH, and T/C-FISH, we thoroughly characterized 59 CLL patients regarding parameters known to be involved in chromosomal instability: status of the genes ATM and TP53 and telomere length. Interestingly, a deletion of the ATM locus in 11q, independent of the cytogenetic context, was associated with significantly diminished risk (p<0.05) of carrying a mutation in TP53. In patients with loss or mutation of TP53, chromosomal breakage occurred more frequently (p<0.01) in (near-) heterochromatic regions. Median telomere length in patients with complex karyotypes was significantly shorter than that of healthy controls and shorter than in all other cytogenetic cohorts. Furthermore, the median telomere length of patients carrying a TP53 mutation was significantly shorter than without mutation. We conclude that telomere shortening in combination with loss of TP53 induces increased chromosomal instability with preferential involvement of (near-) heterochromatic regions.

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Authors and Affiliations

  1. Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str.1, 30625, Hannover, Germany

    Kathrin Thomay, Caroline Fedder, Winfried Hofmann, Brigitte Schlegelberger & Gudrun Göhring

  2. Institute of Pathology, Hannover Medical School, Carl-Neuberg-Str.1, 30625, Hannover, Germany

    Hans Kreipe

  3. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625, Hannover, Germany

    Michael Stadler

  4. Onkologische Praxis Celle, Neumarkt 1, 29221, Celle, Germany

    Jan Titgemeyer

  5. Onkologie am Raschplatz, Rundestr. 10, 30161, Hannover, Germany

    Ingo Zander

Authors
  1. Kathrin Thomay
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  2. Caroline Fedder
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  3. Winfried Hofmann
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  4. Hans Kreipe
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  5. Michael Stadler
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  6. Jan Titgemeyer
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  7. Ingo Zander
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  8. Brigitte Schlegelberger
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  9. Gudrun Göhring
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Correspondence to Gudrun Göhring.

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The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

For this type of study formal consent is not required.

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Informed consent was obtained from all individual participants included in the study.

Funding

This study was funded by the Cluster of Excellence REBIRTH (from Regenerative Biology to Reconstructive Therapy, EXC 6273).

Additional information

Kathrin Thomay and Caroline Fedder shared first authorship

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Thomay, K., Fedder, C., Hofmann, W. et al. Telomere shortening, TP53 mutations and deletions in chronic lymphocytic leukemia result in increased chromosomal instability and breakpoint clustering in heterochromatic regions. Ann Hematol 96, 1493–1500 (2017). https://doi.org/10.1007/s00277-017-3055-1

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  • DOI: https://doi.org/10.1007/s00277-017-3055-1

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